20P - Matrix metalloproteinases and their tissue inhibitors genes abnormal DNA methylation in breast cancer

Abstract

BackgroundMatrix metalloproteinases (MMPs) specifically hydrolyze the extracellular matrix proteins. MMPs are inhibited by tissue inhibitors of MMPs (TIMPs). Changes in the expression levels of MMPs and TIMPs have been described in various cancers, including breast cancer (BC). MethodsWe analyzed methylation status of 11 MMP genes (MMP2, MMP11, MMP14, MMP15, MMP16, MMP17, MMP21, MMP23B, MMP24, MMP25, MMP28) and 4 TIMP genes (TIMP1, TIMP2, TIMP3, TIMP4) in 183 BC samples and 183 matched samples of morphologically normal adjacent tissues, 6 BC cell lines (ZR711, HBL100, HS578T, BT474, T47D, MCF7), and 6 autopsy samples of normal breast tissues by methylation sensitive restriction enzyme digestion PCR (MSRE-PCR).Table20P MMP genes differentially methylated in BCTableGeneMethylated in BC, %Methylated in normal breast tissuesPresence (+) or absence (–) of methylation in BC cell linesZR751MCF7T47DBT474HBL100HS578TMMP27,7 (14/183)0+++---MMP23B17 (31/182)0+++-++MMP2411,9 (20/168)0---++-MMP2515,4 (28/182)0-++-+-MMP284,9 (9/183)0+++++- ResultsIn our collection of BC samples, cancer related abnormal methylation was observed for the MMP2, MMP23B, MMP24, MMP25, and MMP28 genes of the MMPs family (Table). Other MMP genes under study were nonmethylated both in tumors and in normal tissues, as well as the TIMP genes TIMP2 and TIMP3. The promoter regions of TIMP1, TIMP4, MMP14, and MMP21 were found to be constitutively methylated in breast tissues, no matter cancerous or normal. A multiple correspondence analysis demonstrated that nonmethylated status of the promoter regions of MMP2, MMP23B, MMP24, MMP25, MMP28 is associated with lack of HER2 expression. The methylated status of the MMP23B is associated with a higher level (3+) of HER2 expression. Table: MMP genes differentially methylated in BC. ConclusionsTaken that HER2-positive BC is a more aggressive disease, one can assume that unsuppressed expression of the MMP2, MMP23B, MMP24, MMP25, MMP28 genes allowed by the absence of abnormal methylation of their promoters is characteristic for less aggressive BCs. Legal entity responsible for the study: Research Centre for Medical Genetics. Funding: The research was carried out within the state assignment of Ministry of Science and Higher Education of the Russian Federation. Legal entity responsible for the studyResearch Centre for Medical Genetics. FundingMinistry of Science and Higher Education of the Russian Federation. DisclosureAll authors have declared no conflicts of interest.